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Assessing health outcomes associated with exposure to polychlorinated biphenyls (PCBs) is important given their persistent and ubiquitous nature. PCBs are classified as a Group 1 carcinogen, but the full range of potential noncancer health effects from exposure to PCBs has not been systematically summarized and evaluated. We used systematic review methods to identify and screen the literature using combined manual review and machine learning approaches. A protocol was developed that describes the literature search strategy and Populations, Exposures, Comparators, and Outcomes (PECO) criteria used to facilitate subsequent screening and categorization of literature into a systematic evidence map of PCB exposure and noncancer health endpoints across 15 organs/systems. A comprehensive literature search yielded 62,599 records. After electronic prioritization steps, 17,037 studies were manually screened at the title and abstract level. An additional 900 studies identified by experts or supplemental searches were also included. After full-text screening of 3889 references, 1586 studies met the PECO criteria. Relevant study details such as the endpoints assessed, exposure duration, and species were extracted into literature summary tables. This review compiles and organizes the human and mammalian studies from these tables into an evidence map for noncancer health endpoints and PCB mixture exposure to identify areas of robust research as well as areas of uncertainty that would benefit from future investigation. Summary data are available online as interactive visuals with downloadable metadata. Sufficient research is available to inform PCB hazard assessments for most organs/systems, but the amount of data to inform associations with specific endpoints differs. Furthermore, despite many years of research, sparse data exist for inhalation and dermal exposures, which are highly relevant human exposure routes. This evidence map provides a foundation for future systematic reviews and noncancer hazard assessments of PCB mixtures and for strategic planning of research to inform areas of greater uncertainty.

Human health risk assessment currently uses the reference dose or reference concentration (RfD, RfC) approach to describe the level of exposure to chemical hazards without appreciable risk for non-cancer health effects in people. However, this "bright line" approach assumes that there is minimal risk below the RfD/RfC with some undefined level of increased risk at exposures above the RfD/RfC and has limited utility for decision-making. Rather than this dichotomous approach, non-cancer risk assessment can benefit from incorporating probabilistic methods to estimate the amount of risk across a wide range of exposures and define a risk-specific dose. We identify and review existing approaches for conducting probabilistic non-cancer risk assessments. Using perchloroethylene (PCE), a priority chemical for the U.S. Environmental Protection Agency under the Toxic Substances Control Act, we calculate risk-specific doses for the effects on cognitive deficits using probabilistic risk assessment approaches. Our probabilistic risk assessment shows that chronic exposure to 0.004 ppm PCE is associated with approximately 1-in-1,000 risk for a 5% reduced performance on the Wechsler Memory Scale Visual Reproduction subtest with 95% confidence. This exposure level associated with a 1-in-1000 risk for non-cancer neurocognitive deficits is lower than the current RfC for PCE of 0.0059 ppm, which is based on standard point of departure and uncertainty factor approaches for the same neurotoxic effects in occupationally exposed adults. We found that the population-level risk of cognitive deficit (indicating central nervous system dysfunction) is estimated to be greater than the cancer risk level of 1-in-100,000 at a similar chronic exposure level. The extension of toxicological endpoints to more clinically relevant endpoints, along with consideration of magnitude and severity of effect, will help in the selection of acceptable risk targets for non-cancer effects. We find that probabilistic approaches can 1) provide greater context to existing RfDs and RfCs by describing the probability of effect across a range of exposure levels including the RfD/RfC in a diverse population for a given magnitude of effect and confidence level, 2) relate effects of chemical exposures to clinical disease risk so that the resulting risk assessments can better inform decision-makers and benefit-cost analysis, and 3) better reflect the underlying biology and uncertainties of population risks.

The manufacture and production of industrial chemicals continues to increase, with hundreds of thousands of chemicals and chemical mixtures used worldwide, leading to widespread population exposures and resultant health impacts. Low-wealth communities and communities of color often bear disproportionate burdens of exposure and impact; all compounded by regulatory delays to the detriment of public health. Multiple authoritative bodies and scientific consensus groups have called for actions to prevent harmful exposures via improved policy approaches. We worked across multiple disciplines to develop consensus recommendations for health-protective, scientific approaches to reduce harmful chemical exposures, which can be applied to current US policies governing industrial chemicals and environmental pollutants. This consensus identifies five principles and scientific recommendations for improving how agencies like the US Environmental Protection Agency (EPA) approach and conduct hazard and risk assessment and risk management analyses: (1) the financial burden of data generation for any given chemical on (or to be introduced to) the market should be on the chemical producers that benefit from their production and use; (2) lack of data does not equate to lack of hazard, exposure, or risk; (3) populations at greater risk, including those that are more susceptible or more highly exposed, must be better identified and protected to account for their real-world risks; (4) hazard and risk assessments should not assume existence of a "safe" or "no-risk" level of chemical exposure in the diverse general population; and (5) hazard and risk assessments must evaluate and account for financial conflicts of interest in the body of evidence. While many of these recommendations focus specifically on the EPA, they are general principles for environmental health that could be adopted by any agency or entity engaged in exposure, hazard, and risk assessment. We also detail recommendations for four priority areas in companion papers (exposure assessment methods, human variability assessment, methods for quantifying non-cancer health outcomes, and a framework for defining chemical classes). These recommendations constitute key steps for improved evidence-based environmental health decision-making and public health protection.

Glyphosate is the most widely used broad-spectrum systemic herbicide in the world. Recent evaluations of the carcinogenic potential of glyphosate-based herbicides (GBHs) by various regional, national, and international agencies have engendered controversy. We investigated whether there was an association between high cumulative exposures to GBHs and increased risk of non-Hodgkin lymphoma (NHL) in humans. We conducted a new meta-analysis that includes the most recent update of the Agricultural Health Study (AHS) cohort published in 2018 along with five case-control studies. Using the highest exposure groups when available in each study, we report the overall meta-relative risk (meta-RR) of NHL in GBH-exposed individuals was increased by 41% (meta-RR = 1.41, 95% confidence interval, CI: 1.13-1.75). For comparison, we also performed a secondary meta-analysis using high-exposure groups with the earlier AHS (2005), and we calculated a meta-RR for NHL of 1.45 (95% CI: 1.11-1.91), which was higher than the meta-RRs reported previously. Multiple sensitivity tests conducted to assess the validity of our findings did not reveal meaningful differences from our primary estimated meta-RR. To contextualize our findings of an increased NHL risk in individuals with high GBH exposure, we reviewed publicly available animal and mechanistic studies related to lymphoma. We documented further support from studies of malignant lymphoma incidence in mice treated with pure glyphosate, as well as potential links between glyphosate / GBH exposure and immunosuppression, endocrine disruption, and genetic alterations that are commonly associated with NHL or lymphomagenesis. Overall, in accordance with findings from experimental animal and mechanistic studies, our current meta-analysis of human epidemiological studies suggests a compelling link between exposures to GBHs and increased risk for NHL.

BackgroundPhthalates are common plasticizer chemicals that have been linked to glucose intolerance in the general population, but there is only limited research on their association with gestational diabetes (GDM).ObjectiveWe evaluated the association between 11 urinary phthalate metabolites and GDM, impaired glucose tolerance (IGT), and continuous blood glucose concentration during pregnancy in The Infant Development and Environment Study (TIDES). Based on prior study results, our primary analyses focused on monoethyl phthalate (MEP) in relation to our outcomes of interest.Study designWe used multi-variable logistic regression to examine the odds of GDM and IGT in relation to an interquartile-range (IQR) increase in natural log (ln)-transformed, specific gravity (SG)-adjusted first trimester (T1) and average of T1 and third trimester (T3) ("T1T3avg") phthalate metabolite concentrations. We fit linear regression models to examine the percent change in blood glucose per IQR increase in ln-transformed, SG-adjusted T1 and T1T3avg phthalates. In sensitivity analyses, we examined interactions between exposure and race. We adjusted for maternal age, maternal body mass index, study center, race/ethnicity, parity, and gestational age at glucose testing.ResultsIn our sample of 705 pregnant women, we observed 60 cases of GDM, 90 cases of IGT, and an average GLT blood glucose of 113.6 ± 27.7 mg/dL. In our primary analysis, T1T3avg MEP was positively associated with GDM ([OR (95% CI) per IQR increase] T1T3avg MEP: 1.61 (1.10, 2.36)). In secondary analyses, most other phthalates were not found to be related to study outcomes, though some associations were noted. Sensitivity analyses indicated possible strong race-specific associations in Asians, though these results are based on a small sample size (n = 35).ConclusionIn alignment with our a priori selection, we documented an association between T1T3avg MEP and GDM. Additional phthalate metabolites were also found to be linked to glucose intolerance, with possible stronger associations in certain racial/ethnic subgroups. Given the prevalence of phthalate exposures and the growing evidence of associations with metabolic outcomes, future studies should continue to examine this question in diverse cohorts of pregnant women, particularly in those who may be at higher risk for GDM and IGT.

Introduction Neurodegenerative diseases, including Alzheimer's disease (AD) and related dementias (ADRD), pose a growing burden on our rapidly aging society (Livingston et al. 2020). In 2016, dementia was the fifth [...], Background: Air pollution may be associated with elevated dementia risk. Prior research has limitations that may affect reliability, and no studies have evaluated this question in a population-based cohort of men and women in the United States. Objectives: We evaluated the association between time-varying, 10-y average fine particulate matter ([PM.sub.2.5]) exposure and hazard of all-cause dementia. An additional goal was to understand how to adequately control for age and calendar-time-related confounding through choice of the time axis and covariate adjustment. Methods: Using the Adult Changes in Thought (ACT) population-based prospective cohort study in Seattle, we linked spatiotemporal model-based [PM.sub.2.5] exposures to participant addresses from 1978 to 2018. Dementia diagnoses were made using high-quality, standardized, consensus-based protocols at biennial follow-ups. We conducted multivariable Cox proportional hazards regression to evaluate the association between time-varying, 10-y average [PM.sub.2.5] exposure and time to event in a model with age as the time axis, stratified by apolipoprotein E (APOE) genotype, and adjusted for sex, education, race, neighborhood median household income, and calendar time. Alternative models used calendar time as the time axis. Results: We report 1,136 cases of incident dementia among 4,166 individuals with nonmissing APOE status. Mean [mean [+ or -] standard deviation (SD)] 10-y average [PM.sub.2.5] was 10.1 ([+ or -]2.9) [micro]g/[m.sup.3]. Each 1-[micro]g/[m.sup.3] increase in the moving average of 10-y [PM.sub.2.5] was associated with a 16% greater hazard of all-cause dementia [1.16 (95% confidence interval: 1.03, 1.31)]. Results using calendar time as the time axis were similar. Discussion: In this prospective cohort study with extensive exposure data and consensus-based outcome ascertainment, elevated long-term exposure to [PM.sub.2.5] was associated with increased hazard of all-cause dementia. We found that optimal control of age and time confounding could be achieved through use of either age or calendar time as the time axis in our study. Our results strengthen evidence on the neurodegenerative effects of [PM.sub.2.5]. https://doi.org/10.1289/EHP9018

Introduction The Global Burden of Disease Study (GBD), coordinated by the Institute for Health Metrics and Evaluation (IHME), has emerged as the largest systematic, data-driven effort to quantify the magnitude [...], Background: The Global Burden of Disease (GBD) study, coordinated by the Institute for Health Metrics and Evaluation (IHME), produces influential, data-driven estimates of the burden of disease and premature death due to major risk factors. Expanded quantification of disease due to environmental health (EH) risk factors, including climate change, will enhance accuracy of GBD estimates, which will contribute to developing cost-effective policies that promote prevention and achieving Sustainable Development Goals. Objectives: We review key aspects of the GBD for the EH community and introduce the Global Burden of Disease-Pollution and Health Initiative (GBD-PHI), which aims to work with IHME and the GBD study to improve estimates of disease burden attributable to EH risk factors and to develop an innovative approach to estimating climate-related disease burden--both current and projected. Methods: We discuss strategies for improving GBD quantification of specific EH risk factors, including air pollution, lead, and climate change. We highlight key methodological challenges, including new EH risk factors, notably evidence rating and global exposure assessment. Discussion: A number of issues present challenges to the scope and accuracy of current GBD estimates for EH risk factors. For air pollution, minimal data exist on the exposure-risk relationships associated with high levels of pollution; epidemiological studies in high pollution regions should be a research priority. For lead, the GBD's current methods do not fully account for lead's impact on neurodevelopment; innovative methods to account for subclinical effects are needed. Decisions on inclusion of additional EH risk-outcome pairs need to be guided by findings of systematic reviews, the size of exposed populations, feasibility of global exposure estimates, and predicted trends in exposures and diseases. Neurotoxicants, endocrine-disrupting chemicals, and climate-related factors should be high priorities for incorporation into upcoming iterations of the GBD study. Enhancing the scope and methods will improve the GBD's estimates and better guide prevention policy. https://doi.org/10.1289/EHP5496

Introduction The development of the concept of the exposome (Wild 2005) has provided the field of environmental health with the exciting challenge of identifying and measuring the totality of environmental [...], Background: Exposome-related efforts aim to document the totality of human exposures across the lifecourse. This field has advanced rapidly in recent years but lacks practical application to risk assessment, particularly for children's health. Objectives: Our objective was to apply the exposome to children's health risk assessment by introducing the concept of Lifestage Exposome Snapshots (LEnS). Case studies are presented to illustrate the value of the framework. Discussion: The LEnS framework encourages organization of exposome studies based on windows of susceptibility for particular target organ systems. Such analyses will provide information regarding cumulative impacts during specific critical periods of the life course. A logical extension of this framework is that regulatory standards should analyze exposure information by target organ, rather than for a single chemical only or multiple chemicals grouped solely by mechanism of action. Conclusions: The LEnS concept is a practical refinement to the exposome that accounts for total exposures during particular windows of susceptibility in target organ systems. Application of the LEnS framework in risk assessment and regulation will improve protection of children's health by enhancing protection of sensitive developing organ systems that are critical for lifelong health and well-being. https://doi.org/10.1289/EHP1250

Increasing scientific evidence suggests potential adverse effects on children's health from synthetic chemicals used as food additives, both those deliberately added to food during processing (direct) and those used in materials that may contaminate food as part of packaging or manufacturing (indirect). Concern regarding food additives has increased in the past 2 decades in part because of studies that increasingly document endocrine disruption and other adverse health effects. In some cases, exposure to these chemicals is disproportionate among minority and lowincome populations. This report focuses on those food additives with the strongest scientific evidence for concern. Further research is needed to study effects of exposure over various points in the life course, and toxicity testing must be advanced to be able to better identify health concerns prior to widespread population exposure. The accompanying policy statement describes approaches policy makers and pediatricians can take to prevent the disease and disability that are increasingly being identified in relation to chemicals used as food additives, among other uses. [ABSTRACT FROM AUTHOR]

The article offers the authors' response to glyphosate use and cancer incidence in the Agricultural Health Study (AHS). The authors say that exposure assessment in the AHS was complete at baseline, and the study authors used a well-respected approach to fill in missing data. They also urges the AHS investigators to refine their approach and improve the ability to understand the impacts of glyphosate exposure.

Glyphosate is the most widely used broad-spectrum systemic herbicide in the world. Recent evaluations of the carcinogenic potential of glyphosate-based herbicides (GBHs) by various regional, national, and international agencies have engendered controversy. We investigated whether there was an association between high cumulative exposures to GBHs and increased risk of non-Hodgkin lymphoma (NHL) in humans. We conducted a new meta-analysis that includes the most recent update of the Agricultural Health Study (AHS) cohort published in 2018 along with five case-control studies. Using the highest exposure groups when available in each study, we report the overall meta-relative risk (meta-RR) of NHL in GBH-exposed individuals was increased by 41% (meta-RR = 1.41, 95% confidence interval, CI: 1.13-1.75). For comparison, we also performed a secondary meta-analysis using high-exposure groups with the earlier AHS (2005), and we calculated a meta-RR for NHL of 1.45 (95% CI: 1.11-1.91), which was higher than the meta-RRs reported previously. Multiple sensitivity tests conducted to assess the validity of our findings did not reveal meaningful differences from our primary estimated meta-RR. To contextualize our findings of an increased NHL risk in individuals with high GBH exposure, we reviewed publicly available animal and mechanistic studies related to lymphoma. We documented further support from studies of malignant lymphoma incidence in mice treated with pure glyphosate, as well as potential links between glyphosate / GBH exposure and immunosuppression, endocrine disruption, and genetic alterations that are commonly associated with NHL or lymphomagenesis. Overall, in accordance with findings from experimental animal and mechanistic studies, our current meta-analysis of human epidemiological studies suggests a compelling link between exposures to GBHs and increased risk for NHL., (Copyright © 2019 Elsevier B.V. All rights reserved.)